PROJECT SUMMARY/ABSTRACT Advances in the effectiveness of breast cancer screening and treatment have reduced the breast cancer mortality rate over the last decades. These advances come from avoided recurrences, but also from delayed recurrences. The success of chemotherapy, endocrine therapy, and radiation therapy, is typically measured by a reduction in the risk of recurrence in the first five years after breast cancer diagnosis. Many recurrences, however, occur late; that is, more than five years after diagnosis. These recurrences erupt from single dormant cells or micro-metastases where tumor cell growth has been balanced by tumor cell death. How does a single cell, or a small colony of cells, survive for more than five years in a hostile microenvironment that, at least at the outset, often includes hypoxic climates induced by cancer therapies? One likely explanation is that tumors with the capability to recruit stanniocalcin are more likely to survive in this setting and to recur five or more years after diagnosis. Stanniocalcin is a hormone first discovered in bony fish, where it regulates the concentration of calcium at the gills. In humans, nerve cells, fat cells, heart cells, ova, and other long-lived cells recruit stanniocalcin as a survival strategy when they face hypoxic stress, helping them to live in sometimes harsh conditions by uncoupling proton transport from glycosylation in the mitochondria. Preliminary human evidence and in vitro studies show that tumor expression of stanniocalcin is a marker of recurrence risk, and particularly late recurrence risk. We propose, therefore, to use an existing biobank from ~1700 breast cancer patients (841 with recurrence and 841 matched controls) linked to complete clinical data and long-term follow-up for recurrence to investigate whether stanniocalcin expression is a specific marker for late recurrence risk. We will determine whether breast cancer patients with late recurrences were more likely to have had primary tumors that express stanniocalcin than breast cancer patients with early recurrences. We will also determine whether the tumor cells of those with late recurrence are more likely to have retained or acquired the ability to express stanniocalcin than the tumor cells of those with early recurrence. If we find that stanniocalcin is a specific marker for late breast cancer recurrence, we will seek new research support to validate the result in a second breast cancer cohort and in a colorectal cancer cohort, and to investigate drugs to disrupt the pathway. There is no specific marker for late recurrence risk. A marker that predicts when a recurrence will occur, rather than whether a recurrence will occur, would change the clinical paradigm for cancers with substantial late recurrence risk. It would allow personalization of recurrence screening strategies, development of low- toxicity prophylactic therapies that begin when the late recurrence risk rises, and personalization of existing adjuvant therapies with regard to time from diagnosis. This R21 high-risk, high-reward project will initiate a program to identify markers of late recurrence risk and strategies to reduce or ameliorate that risk.